Testosterone restores respiratory long term facilitation in old male rats by an aromatase‐dependent mechanism

Abstract

Non-technical summary Steroidal sex hormones (testosterone, oestradiol and progesterone) play an important role in the neural control of breathing. Hormone levels typically change throughout life. Testosterone levels increase during puberty in boys, but from ∼30 years of age levels decline gradually. The typical age of onset for obstructive sleep apnoea, a prominent breathing disorder of older humans, is ∼50 years of age in men. In a study in old male rats, we show that testosterone supplementation can reverse the age-associated decrease in one measurement of the neural control of breathing. We conclude that testosterone supplementation can potentially be used to enhance upper airway function in the elderly.Abstract Steroidal sex hormones play an important role in the neural control of breathing. Previous studies in our laboratory have shown that gonadectomy in young male rats (3 months) eliminates a form of respiratory plasticity induced by intermittent hypoxia, known as long term facilitation (LTF). Testosterone replenishment restores LTF in gonadectomized male rats, and this is dependent on the conversion of testosterone to oestradiol by aromatase. By middle age (12 months), male rats no longer exhibit LTF of hypoglossal motor output; phrenic LTF is significantly reduced, and this persists into old age. We tested the hypothesis that LTF can be restored in old male rats by administration of testosterone. Intact Fischer 344 rats (>20 months) were implanted with Silastic tubing containing testosterone (T), T plus an aromatase inhibitor (T+ADT), or 5α-dihydrotestosterone (DHT), a form of testosterone not converted to oestradiol. One week post-surgery, LTF of hypoglossal and phrenic motor output was measured. By comparison with control rats, hypoglossal LTF was increased in testosterone-treated rats, with levels approaching that of normal young rats. LTF was not restored in T+ADT or DHT-treated rats. Aromatase levels in hypoglossal and phrenic nuclei did not change with age. As serum testosterone levels did not decline with age, local bioavailability of testosterone in old rats may be a limiting factor in the expression of this form of respiratory plasticity. Our findings suggest that testosterone supplementation could potentially be used to enhance upper airway control in the elderly. Abbreviations ADT, 1,4,9-androstatriene-3,17-dione; AR, androgen receptor; BDNF, brain-derived neurotrophic factor; DHT, 5α-dihydrotestosterone; E 2 , oestradiol; ER, oestrogen receptor; LTF, long term facilitation; MAP, mean arterial pressure; OSA, obstructive sleep apnoea; SHBG, sex hormone binding globulin; T, testosterone; TrkB, tyrosine kinase B; XII, hypoglossal; %BL, percentage change in peak integrated nerve amplitude from baseline; Phr, peak integrated phrenic amplitude; XII, peak integrated hypoglossal amplitude.

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

“…Research has demonstrated that the magnitude of phrenic nerve LTF is markedly reduced in aged male Sprague-Dawley rats (13months) relative to young male rats (3–4 months), while LTF of the hypoglossal nerve is abolished in the older population (428). This effect has been linked to the expression of sex hormones, and LTF of the phrenic and hypoglossal nerves is similarly abrogated in gonadectomized or aged male Fischer 344 rats relative to young intact animals, such that (i) the decrease in hypoglossal LTF correlates with decreased expression of the sex hormones testosterone, progesterone, and oestradiol (429), and (ii) testosterone supplementation reverses the effects of gonadectomy (430), or aging (277). Furthermore, the expression of LTF has also been shown to vary between various strains of rats, such that AIH-induced changes in 5-HT signaling and LTF of the phrenic and hypoglossal nerves are not observed in Brown Norway rats, but are more pronounced in Lewis rats relative to Fischer 344 rats (17, 128).…”

The impact of inflammation on respiratory plasticity

“…pLTF is diminished with age in male rats (Zabka et al, 2001) and testosterone restores hypoglossal LTF (Nelson et al, 2011). In female rats, pLTF is enhanced with age (Zabka and Behan, 2001) and both male and female elderly rats display increased pLTF after CIH (McGuire et al, 2003; Zabka et al, 2003).…”

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

“…In fact, the long-term facilitation of respiratory motor output in gonadectomized male rats induced by testosterone is dependent on the conversion of testosterone to oestradiol by aromatase. 99 However, testosterone per se increases sleep apnoeas, inducing hypoventilation. In addition, sleep fragmentation eliminates ventilatory long-term facilitation and attenuates HCVR.…”